People with Innate Resistance to HIV Could Provide a Functional HIV Cure

In the process of studying HIV-infected patients who naturally don’t need therapy to control the virus, scientists have found what could become a functional cure for HIV infections.

A team of researchers from France, Italy, the UK and Australia has identified a molecule that could be transferred to HIV-positive people to help their immune system find and destroy HIV-infected cells. Their research has been published today in the journal Science Immunology.

The molecule has been identified by studying HIV controllers: HIV-positive individuals whose immune system naturally builds a strong response to the HIV virus. Comprising less than 0.5% of all HIV-infected people, HIV controllers do not need antiretroviral therapy to keep AIDS symptoms at bay.

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The researchers were looking specifically at immune cells called CD4+ T cells, whose role in the immune response of HIV controllers is still not well understood. “We observed that CD4+ T cell responses were of high sensitivity in the HIV controllers, meaning that CD4+ T cells of these patients could recognize minute amounts of viral antigens,” said Lisa Chakrabarti, researcher at the Pasteur Institute in Paris and one of the authors of the study.

What she and the team found was that this response was driven by T cell receptors (TCRs) on the surface of the CD4+ T cells that bind to a protein of the capsid that envelops the HIV virus, called Gag. “We were able to characterize TCRs with remarkably high affinity for this Gag peptide, in the highest range of the affinities reported for human TCRs,” said Chakrabarti.

Out of eight HIV controllers, the scientists found identical TCRs against this HIV protein in six of them, which is remarkable given that each human has about 20 million different TCRs and they are rarely identical between two individuals.

The researchers believe this TCR could be transferred to the T cells of HIV-infected patients to help them fight the virus as HIV controllers do. They have shown that genetically engineering the T cells of healthy donors made them able to kill HIV-infected cells in a petri dish. The next step will be to test whether these results can also be observed in mice transplanted with a model human immune system.

“If we obtain a proof of concept in the animal model, we will aim at developing a TCR immunotherapy that could benefit HIV infected patients,” said Chakrabarti. “The idea would be to harvest patient T cells, to transfer a public TCR to these T cells, and to reinfuse the T cells to the patient.”

Immunotherapies based on TCRs have become a popular experimental approach in the fight against cancer, and their use in HIV is not a new idea. In the UK, the biotech company Immunocore also has shown that its TCRs can kill HIV-infected cells in the lab, its research being funded with investment from Bill Gates.

One issue with using TCRs to develop immunotherapies is that often these molecules only recognize the antigen when it is presented by a specific HLA molecule on the surface of immune cells. Each person has a different set of HLA molecules, meaning one TCR is only valid for those people with the specific HLA it targets.

However, the TCRs identified in the new study have the rare feature of being able to bind to the viral antigen in multiple types of HLA molecules. “The TCRs studied here are able to recognize five different HLA molecules that cover about 25% of the population. We are now in the process of extending our study to determine how many more HLA molecules those TCRs can recognize,” said Stephanie Gras, researcher at Monash University in Australia.

Although it is still in a very early stage, the research shows potential for the development of an alternative to antiretroviral therapy, which is expensive and can come with severe side effects in the long-term. “The aim is to establish a state of “functional cure” to avoid the need for lifelong antiretroviral therapy. It could also help limit chronic inflammation in patients who remain under ART,” said Chakrabarti.

A functional HIV cure, that is, a treatment that takes away the symptoms of AIDS despite not completely eliminating the virus, is currently the most ambitious goal of HIV research. The efforts of scientists worldwide are now taking us closer to the day when the first functional cure becomes available to HIV-positive people. Something that could happen sooner than one might think.

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